Transcript Protecting cognitive function in hematological cancers

Pooled 24-week results of DUET-1 and DUET-2:
TMC125 (etravirine; ETR) versus placebo
in treatment-experienced HIV-1-infected patients
P Cahn, R Haubrich, J Leider, G Pialoux, M Schechter, S Walmsley,
J Vingerhoets, M Peeters, G De Smedt, MP de Béthune and B Woodfall
on behalf of the DUET-1 and DUET-2 study groups
DUET study design
and major inclusion criteria
Screening
6 weeks
48-week treatment period
with optional 48-week extension
Follow up
4 weeks
24-week primary analysis
600 patients
target per trial
TMC125 + BR*
Placebo + BR*
*BR = darunavir/ritonavir with optimised NRTIs and optional enfuvirtide
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DUET-1 and -2 differed only in geographical location; pooled analysis was pre-specified
Plasma viral load >5,000 HIV-1 RNA copies/mL and stable therapy for ≥8 weeks
≥1 NNRTI RAM, at screening or in documented historical genotype
≥3 primary PI mutations at screening
Patients recruited from Thailand, Australia, Europe and the Americas
BR = background regimen; RAM = resistance-associated mutation
Baseline characteristics
and background ARVs
Parameter,
% or median (range)
TMC125 + BR
(n=599)
Placebo + BR
(n=604)
90
70
89
70
4.8 (2.7–6.8)
99 (1.0–789)
58
4.8 (2.2–6.5)
109 (0.0–912)
59
Prior ARV use 10–15 ARVs (%)
Darunavir/r (%)
Detectable
≥2 NNRTI RAMs* (%)
mutations
≥4 primary PI RAMs (%)
66
4
66
62
64
5
66
63
Background
regimen
46
26
17
36
47
27
16
39
Male (%)
Patient
demographics Caucasian (%)
Disease
Viral load (log10 copies/mL)
characteristics CD4 cells (cells/mL)
CDC category C (%)
Used enfuvirtide (total; %)
Used enfuvirtide de novo (%)
Active background agents§ = 0 (%)
Active background agents§ = 1 (%)
*from extended NNRTI RAM list (Tambuyzer et al. Abstract 67 EHDRW 2007); §assessed by phenotypic
sensitivity score (PSS); BR = background regimen; RAM = resistance-associated mutation
Patients with viral load <50 copies/mL
at Week 24 (primary endpoint; ITT TLOVR)
Responders (%) ± 95% CI
100
TMC125 + BR (n=599)
Placebo + BR (n=604)
90
80
p<0.0001
70
60
59%
50
41%
40
30
20
10
0
0
4
8
12
16
20
24
Time (weeks)
BR = background regimen; CI = confidence interval;
ITT = intent-to-treat population; TLOVR = time to loss of virologic response imputation algorithm
Viral load reduction from baseline
(ITT NC=F)
Mean change in viral load from
baseline (log10 copies/mL) ± SE
0.0
TMC125 + BR (n=599)
Placebo + BR (n=604)
–0.5
–1.0
p<0.0001
–1.5
–1.7
–2.0
–2.4
–2.5
–3.0
–3.5
0
4
8
12
16
20
24
Time (weeks)
BR = background regimen; SE = standard error;
ITT = intent-to-treat population; NC=F = noncompleter equals failure imputation algorithm;
changes below the detection limit (<50 copies/mL) were imputed as 49 copies/mL
Mean change in CD4 cell count
from baseline (cells/mm3) ± SE
Change in CD4 cell count
from baseline (ITT NC=F)
100
+86
75
+67
p<0.0001
50
25
TMC125 + BR (n=599)
Placebo + BR (n=604)
0
0
4
8
12
Time (weeks)
16
20
24
BR = background regimen; SE = standard error;
ITT = intent-to-treat population; NC=F = noncompleter equals failure imputation algorithm
Response (<50 copies/mL) according
to enfuvirtide use (primary analysis)
TMC125 + BR (n=599)
p<0.0001
p=0.427
Patients with viral load
<50 copies/mL at Week 24 (%)
80
p<0.05
73%
67%
62%
60
Placebo + BR (n=604)
62%
56%
Using de novo ENF
40
20
DRV FC
TMC125 Placebo
category, % + BR
+ BR
34%
Adjusted for
differences in
baseline DRV
FC between
groups
Unadjusted
response
rates
<2
20
27
2–10
40
39
10–40
26
26
>40
15
8
0
Re-using or not
using ENF
Using de
novo ENF
Using de
novo ENF
DRV = darunavir
FC = baseline fold change
Response (<50 copies/mL) according
to number of active background ARVs
Number of fully active
background ARVs (PSS)
TMC125 + BR (n=545)
45%
40/88
0
7/91
Placebo + BR (n=559)
8%a
60%
120/199
1
30%
63/211
74%
67%
191/258
≥2
171/257
0
20
40
60
80
100
Patients with viral load <50 copies/mL at Week 24 (%)
Analysis excludes patients who discontinued except for virological failure; PSS = phenotypic sensitivity
score; darunavir and enfuvirtide are counted as fully active if FC<10 or used de novo, respectively
Mutations associated with a
decreased response to TMC125
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13 baseline NNRTI RAMs were associated with a decreased response to
TMC125 (TMC125 RAMs):
V90I
A98G
L100I
K101E/P
V106I
V179D/F
Y181C/I/V
G190A/S
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These RAMs seldom occurred in the absence of other NNRTI RAMs
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K103N is not associated with resistance to TMC125
A decreased response was defined as ≤75% of the response for patients with zero NNRTI RAMs at
baseline from the extended NNRTI RAM list; RAM = resistance-associated mutation
Number of TMC125 RAMs
present at baseline
Response (<50 copies/mL) according
to number of TMC125 RAMS
TMC125 + BR (n=406)
0
121/161
64/147
1
73/121
59/157
2
37/64
17/68
3
13/32
6/24
7/28
3/18
≥4
0
Placebo + BR (n=414)
75%
44%
60%
38%
58%
25%
41%
25%
25%
17%
20
40
60
80
Patients with viral load <50 copies/mL at Week 24 (%)
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The greatest added benefit in the TMC125 versus placebo group was seen in patients
with <3 TMC125 RAMs
86% of patients had <3 TMC125 RAMs
Analysis excludes patients who used de-novo enfuvirtide or discontinued except for virological failure
BR = background regimen; RAM = resistance-associated mutation;
Proportion of patients with any
new AIDS-defining illness or death
Patients with any new AIDSdefining illness or death (%)
TMC125 + BR (n=599)
Placebo + BR (n=604)
10
8
6.8%
6
3.7%
4
2
22/599
0
41/604
Overall population
p=0.4419
BR = background regimen
Proportion of patients with any
new AIDS-defining illness or death
Patients with any new AIDSdefining illness or death (%)
TMC125 + BR (n=599)
Placebo + BR (n=604)
10
8.3%
8
6.8%
6
3.7%
3.8%
4
2
22/599
0
41/604
17/446
37/444
Overall population
Re-using or not using ENF
p=0.4419
p=0.0051
ENF = enfuvirtide; BR = background regimen
Overview of adverse events
(AEs; regardless of causality)
Parameter, %
Any AE (any cause)
Grade 3/4 AE
Discontinuation due to AE
Serious AE
Death (any cause), % (n)
Most
Rash (any type)
common Diarrhea
AEs‡
Nausea
Headache
Nervous system disorders
AEs of
interest Psychiatric disorders
Hepatic AEs
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TMC125 + BR
(n=599)
Placebo + BR
(n=604)
93
93
25
5.8
13
1.3 (8)*
27
4.5
19
2.5 (15)
17§
15
14
9
15
13
5
9
20
11
12
19
15
5
There were no consistent or clinically relevant trends in laboratory, vital signs or ECG data
The profile of laboratory abnormalities, including hepatic and lipid parameters, was
generally similar between the TMC125 and placebo groups
*no deaths in the TMC125 group were considered at least possibly related to trial medication;
‡ in >10% patients in either group, excluding injection site reactions; §p=0.0001 vs placebo
Summary of rash in the
TMC125 group
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Overall incidence: 17% in TMC125 group versus 9% in placebo group
(p=0.0001)
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Early onset: most frequent in 2nd week of therapy; median onset Day 12
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Short duration: median duration 11 days
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Usually mild to moderate severity: 1.3% grade 3 and no grade 4 events
–
no rashes with mucosal involvement
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Infrequently lead to discontinuation
–
2.2% of patients permanently discontinued
–
most self-limiting with continued treatment
Higher incidence in women, but no clear difference in severity or treatment
discontinuations according to gender
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No association with baseline CD4 cell count
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No increased risk in patients with a history of NNRTI-related rash
Conclusions
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In treatment-experienced patients, including those with NNRTI resistant virus,
TMC125 consistently demonstrated superiority over placebo
–
59% of patients achieved confirmed undetectable VL (<50 copies/mL) with
TMC125 plus BR at Week 24
Even in the absence of any other fully active background agents, with
TMC125, 45% of patients achieved undetectable (<50 copies/mL)
viral load
–
response rates increased as more active agents were used in the
background regimen
13 TMC125 resistance-associated mutations (TMC125 RAMs) were identified
–
the greatest added benefit in the TMC125 versus placebo group was
seen in patients with <3 TMC125 RAMs
–
86% patients had <3 TMC125 RAMs
Except for rash, incidence and severity of AEs with TMC125 were similar to
placebo
TMC125 has the ability to extend and enhance the NNRTI class and provide a
new treatment option for patients with resistance to other NNRTIs
Acknowledgements

We express our gratitude to the patients that participated in the study, as well as the
study centre staff, DSMB, clinical event adjudication panel, Virco, Tibotec personnel and
the following principal investigators:
DUET-1
DUET-2
Argentina: H Ariza, J Benetucci, L Calanni,
L Cassetti, J Corral, D David, A Krolewiecki,
M Losso, P Patterson, R Teijeiro; Brazil: C A da
Cunha, B Grinsztejn, E Kallas, JV Madruga,
E Netto, J H Pilotto, J Suleiman, A Timerman;
Chile: J Ballesteros, R Northland; Costa Rica:
A Alvilés Montoya, G Herrera Martinez, A Solano
Chinchilla; France: M Dupon, C Katlama,
J M Livrozet, P Morlat, C Piketty, I Poizot-Martin;
Mexico: J Andrade-Villanueva, G Reyes-Terán,
J Sierra-Madero; Panama: A Canton, A Rodriguez,
N Sosa; Puerto Rico: J O Morales Ramirez,
J L Santana Bagur, R Soto-Malave; Thailand:
T Anekthananon, P Mootsikapun, K Ruxrungtham;
USA: M Albrecht, N Bellos, R Bolan, P Brachman,
C Brinson, F Cruickshank, R Elion, W J Fessel,
T Hawkins, S Hodder, T Jefferson, H Katner,
C Kinder, M Kozal, J Lalezari, D McDonough,
A Mills, K Mounzer, D Norris, W O’Brien, G Pierone,
K Raben, B Rashbaum, M Rawlings, B Rodwick,
P Ruane, J Sampson, S Schrader, A Scribner,
M Sension, D Sweet, B Wade, D Wheeler, A Wilkin,
T Wilkin, T Wills, M Wohlfeiler, K Workowski.
Australia: J Chuah, D Cooper, B Eu, J Hoy, C Workman;
Belgium: N Clumeck, R Colebunders, M Moutschen;
Canada: J Gill, K Gough, P Junod, D Kilby, J Montaner,
A Rachlis, B Trottier, C M Tsoukas; France: C Arvieux,
L Cotte, J F Delfraissy, P M Girard, C Katlama,
B Marchou, J M Molina, D Vittecoq, Y Yazdanpanah,
P Yeni; Germany: K Arasteh, S Esser, G Fätkenheuer,
H Gellermann, K Göbels, F D Goebel, H Jäger, A Moll,
J K Rockstroh, D Schuster, S Staszewski, A Stoehr; Italy:
A Antinori, G Carosi, G Di Perri, R Esposito, A Lazzarin,
F Mazzotta, G Pagano, E Raise, S Rusconi, L Sighinolfi,
F Suter; Netherlands: P H J Frissen, J M Prins,
B J A Rijnders; Poland: A Horban; Portugal: F Antunes,
M Miranda, J Vera; Spain: B Clotet, P Domingo,
G Garcia, J M Gatell, J González-Lahoz, J LópezAldeguer, D Podzamczer; UK: P Easterbrook, M Fisher,
M Johnson, C Orkin, E Wilkins; USA: B Barnett, J Baxter,
G Beatty, D Berger, C Borkert, T Campbell, C Cohen,
M Conant, J Ernst, C Farthing, T File, M Frank,
J E Gallant, A E Greenberg, C Hicks, D T Jayaweera,
S Kerkar, N Markowitz, C Martorell, C McDonald,
D McMahon, M Mogyoros, R A Myers Jr, G Richmond,
K Sathasivam, S Schneider, H Schrager, P Shalit,
F P Siegal, L Sloan, K Smith, S Smith, P Tebas,
L S Tkatch, W Towner.